Bone formation in vertebrates is a dynamic process, involving continuous production of bone and continuous bone resorption. Osteopenia is a general term used to describe any bone-wasting disease in which the rate of bone resorption is greater than the rate of bone formation. Osteoporosis, a bone-wasting disease characterized by a net loss of bone mass due to increased bone resorption exceeding bone formation, is a common disorder affecting millions of people throughout the world. In osteoporosis, the skeleton become weakened and unable to bear the normal stresses imposed on it. The effects of the disease are therefore generally seen in the parts of the skeleton that are weight-bearing, especially the spine and hips, which can fracture in the absence of trauma.
Among the drugs that have been used to treat bone-wasting diseases is sodium fluoride, which has been shown to stimulate bone formation in vivo by a direct mitogenic effect on bone cells. Bone mineral density of the axial skeleton of patients treated with fluoride increases, and the serum alkaline phosphatase level, an index of bone formation in the skeleton, also increases. Significant increases in spinal bone density are seen after about 12-18 months of fluoride therapy. However, fluoride treatment is not equally effective in all patients, as some patients respond poorly to fluoride (showing only small increases in bone mineral density) and others do not respond at all.
Dilantin (also known as phenytoin or diphenylhydantoin) is a known anti-convulsant drug used extensively in the treatment of grand mal and psychomotric epilepsy. Clinical data relating dilantin to effects on bone are mixed. Some studies in mouse calvaria in culture have shown a stimulation of fibroblast proliferation and an ability to inhibit parathyroid hormone and prostaglandin E2-stimulated bone resorption. One study of patients on dilantin therapy also indicated significantly less mean bone loss than a control group of patients receiving no dilantin. However, other studies have shown that dilantin can actually cause osteoporosis, perhaps by producing vitamin D deficiency. Accordingly, the effects of dilantin on net bone formation or loss are inclusive.
In addition to fluoride treatment, there are a number of other techniques that have been suggested for increasing bone mass, including use of 1,25-dihydroxy vitamin D and other growth-promoting substances, but these treatments have met with mixed success.
A number of these problems were overcome by an invention previously made by the present inventor and described in U.S. Pat. application Ser. No. 07/080,759, filed Aug. 3, 1987, now a U.S. Pat. No. 4,911,931 which is herein incorporated by reference. That earlier invention provides a pharmaceutical composition useful for increasing bone mass and/or preventing loss of bone mass in vertebrates. The composition comprises a fluoride source and a mitogenic hydantoin (typically a 5-aromatic-substituted hydantoin) in combination with a pharmaceutically acceptable carrier. By providing a hydantoin in combination with a fluoride source, significant increases are seen in bone formation over untreated controls or controls treated with fluoride alone. Additionally, the combination has been shown to improve spinal bone density in all patients treated, including those who are normally poor responders to fluoride alone.
However, it was thought when the earlier application was filed that a molar ratio of fluoride (not fluoride source, since the fluoride source does not necessarily produce only one fluoride ion per molecule) to the hydantoin of at least 1:1 was required in order to produce the desired increase. There does not appear to be any upper limit on the molar ratio of fluoride ion to hydantoin, although typically the molar ratio will be less than 1000:1. It is has now been discovered that lower ratios of fluoride to hydantoin are effective and may be used, particularly in view of the tendency toward administering lower amount of fluoride in order to avoid adverse side effects.
Accordingly, there remains a need for a practical pharmaceutical composition capable of increasing the rate of bone formation, particularly a composition that is effective on patients that are normally not responsive to treatment with fluoride, which uses relatively low levels of fluoride.